A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I

Daniel C Mendez; Alexander E Stover; Anthony D Rangel; David J Brick; Hubert E Nethercott; Marissa A Torres; Omar Khalid; Andrew MS Wong; Jonathan D Cooper; James V Jester; Edwin S Monuki; Cian McGuire; Steven Q Le; Shih-hsin Kan; Patricia I Dickson; Philip H Schwartz

Molecular Therapy: Methods & Clinical Development (Jan 2015)

A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I

Daniel C Mendez,
Alexander E Stover,
Anthony D Rangel,
David J Brick,
Hubert E Nethercott,
Marissa A Torres,
Omar Khalid,
Andrew MS Wong,
Jonathan D Cooper,
James V Jester,
Edwin S Monuki,
Cian McGuire,
Steven Q Le,
Shih-hsin Kan,
Patricia I Dickson,
Philip H Schwartz

Affiliations

Daniel C Mendez: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Alexander E Stover: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Anthony D Rangel: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
David J Brick: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Hubert E Nethercott: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Marissa A Torres: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Omar Khalid: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA
Andrew MS Wong: King's College, London, Institute of Psychiatry, Psychology & Neuroscience, London, UK
Jonathan D Cooper: King's College, London, Institute of Psychiatry, Psychology & Neuroscience, London, UK
James V Jester: Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, California, USA; Department of Biomedical Engineering, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, California, USA
Edwin S Monuki: Department of Pathology and Laboratory Medicine, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA; Department of Developmental and Cell Biology, Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, California, USA
Cian McGuire: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
Steven Q Le: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
Shih-hsin Kan: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
Patricia I Dickson: Division of Medical Genetics, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA
Philip H Schwartz: National Human Neural Stem Cell Resource, Centers for Neuroscience and Translational Research, CHOC Children's Research Institute, Orange, California, USA

Journal volume & issue: Vol. 2

Abstract

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Mucopolysaccharidosis type I (MPS I) is an inherited Î±-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rÎ³ (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches.

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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